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不确定期慢性HBV感染者发生显著肝组织病理学损伤的危险因素分析
DOI: 10.12449/JCH251110
伦理学声明：本研究方案于2024年10月8日经由中国人民解放军总医院第五医学中心伦理委员会审批，批号：KY-2024-10-156-1。
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：王文畅负责设计论文框架，起草论文；李旭阳、王春艳、付懿铭负责数据收集；贺梦雯负责统计学分析；郭忆凡负责绘制图表；刘淼负责拟定写作思路；纪冬负责指导撰写文章并最后定稿。
High-risk factors for significant liver histopathological damage in patients with indeterminate phase of chronic HBV infection
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摘要:
目的 分析不确定期慢性HBV感染者肝组织病理学损伤特点，探讨此类患者启动抗病毒治疗的时机。 方法 回顾性筛选2018年3月—2022年4月在中国人民解放军总医院第五医学中心住院并接受肝活检的慢性HBV感染者，纳入其中符合《慢性乙型肝炎防治指南（2022年版）》定义的不确定期者，收集其临床资料。肝组织病理学分期基于Scheuer标准，将炎症程度（G）分为0～4期，纤维化程度（S）分为0～4期，按照存在显著炎症（≥G2）及存在显著纤维化（≥S2）分别进行分组。正态分布的计量资料2组间比较采用成组t检验；非正态分布计量资料2组间比较采用Mann-Whitney U 检验；计数资料2组间比较采用χ2检验或Fisher确切概率法。采用Spearman秩相关分析探讨肝组织病理学与临床因素之间的关联，通过Logistic回归模型筛选显著炎症和肝纤维化的独立影响因素。 结果 共纳入271例不确定期慢性HBV感染者，61例（22.5%）存在显著炎症，124例（45.8%）存在显著肝纤维化。Logistic回归分析显示，ALT≥30/19 U/L（男/女）（OR=2.69， 95%CI：1.39～5.21，P=0.003）、HBV DNA≥2 000 IU/mL（OR=2.75， 95%CI：1.38～5.48，P=0.004）以及LSM≥6.0 kPa（OR=4.57， 95%CI：2.17～9.62，P<0.001）是显著炎症的独立风险因素。HBV DNA≥2 000 IU/mL（OR=1.82， 95%CI：1.01～3.32， P=0.049）以及LSM≥6.0 kPa（OR=2.06， 95%CI：1.23～3.43， P=0.006）是显著肝纤维化的独立影响因素。 结论 不确定期慢性HBV感染者中有较高比例的患者具有显著肝组织病理学改变，具有高危因素的患者需要及时启动抗病毒治疗。 Abstract:Objective To investigate the features of liver histopathological damage in patients with indeterminate phase of chronic HBV infection， as well as the timing for initiating antiviral therapy in such patients. Methods A retrospective screening was performed for the patients with chronic HBV infection who were hospitalized in The Fifth Medical Center of Chinese PLA General Hospital and underwent liver biopsy from March 2018 to April 2022， among whom the patients who met the criteria for indeterminate phase defined in Chinese guidelines for chronic hepatitis B prevention and treatment （2022 edition） were enrolled， and their clinical data were collected. Liver histopathological stage was determined using the Scheuer scoring system， with stages 0 — 4 for inflammation grade （G） and stages 0 — 4 for fibrosis degree （S）， and the patients were divided into groups based on the presence of significant necroinflammation （≥G2） and significant liver fibrosis （≥S2）. The independent samples t-test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. A Spearman’s rank correlation analysis was used to investigate the correlation between liver histopathology and clinical factors， and the Logistic regression model was used to identify the independent influencing factors for significant necroinflammation and liver fibrosis. Results A total of 271 patients with indeterminate phase of chronic HBV infection were enrolled， among whom 61 （22.5%） had significant necroinflammation （≥G2） and 124 （45.8%） had significant liver fibrosis （≥S2）. The Logistic regression analysis showed that alanine aminotransferase ≥30 U/L （for male patients） or ≥19 U/L （for female patients） （odds ratio ［OR］=2.69， 95% confidence interval ［CI］： 1.39 — 5.21， P=0.003）， HBV DNA ≥2 000 IU/mL （OR=2.75， 95%CI： 1.38 — 5.48， P=0.004）， and liver stiffness measurement （LSM） ≥6.0 kPa （OR=4.57， 95%CI： 2.17 — 9.62， P<0.001） were independent risk factors for significant inflammation. HBV DNA ≥2 000 IU/mL （OR=1.82， 95%CI： 1.01 — 3.32， P=0.049） and LSM ≥6.0 kPa （OR=2.06， 95%CI： 1.23 — 3.43， P=0.006） were independent influencing factors for significant liver fibrosis. Conclusion Among the patients with indeterminate phase of chronic HBV infection， a substantial proportion of patients have significant liver histopathological damage. Antiviral therapy should be initiated in a timely manner for patients with high-risk factors. -
Key words:
- Hepatitis B Virus /
- Inflammation /
- Hepatic Fibrosis /
- Indeterminate Phase
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图 1 不同无创检测指标与肝脏炎症及肝纤维化的相关性
Figure 1. Correlation between diverse noninvasive modalities and hepatic inflammation with fibrosis progression
图 2 不同无创检测指标与肝脏显著炎症的关系
Figure 2. Association of different non-invasive tests and grouping with significant hepatic inflammation
表 1 纳入患者按照肝脏炎症程度分组的一般特征
Table 1. General characteristics of enrolled patients grouped by the degree of hepatic inflammation
指标 总计（n=271） G0～1（n=210） ≥G2（n=61） 统计值 P值 男［例（%）］ 171（63.1） 131（62.4） 40（65.6） χ2=0.21 0.649 年龄（岁） 41.0±10.6 41.3±10.1 39.8±12.2 t=0.90 0.371 HBV DNA（log10 IU/mL） 3.7±1.4 3.5±1.4 4.1±1.6 t=2.33 0.022 LSM （kPa） 6.2（5.1～8.0） 6.1（5.1～7.2） 8.1（6.5～12.5） Z=5.70 <0.001 ALT （U/L） 24.3±8.2 23.3±8.2 27.8±7.3 t=3.93 <0.001 AST （U/L） 24.7±7.9 22.9±5.9 30.9±10.4 t=5.74 <0.001 Alb （g/L） 41.2±2.7 41.4±2.6 41.0±3.0 t=0.89 0.377 PLT （×109/L） 178.5±56.3 182.6±54.3 164.2±61.1 t=2.27 0.024 
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表 2 纳入患者按照肝纤维化程度分组的一般特征
Table 2. General characteristics of the enrolled patients grouped by the degree of hepatic fibrosis
指标 S0～1（n=147） ≥S2（n=124） 统计值 P值 男［例（%）］ 90（61.2） 81（65.3） χ2=0.49 0.486 年龄（岁） 40.8±10.1 41.2±11.1 t=0.30 0.765 HBV DNA（log10 IU/mL） 3.6±1.4 3.8±1.5 t=1.05 0.294 LSM （kPa） 6.1（4.9～7.3） 6.8（5.5～9.1） Z=3.53 <0.001 ALT （U/L） 23.7±8.3 25.0±8.0 t=1.34 0.181 AST （U/L） 24.3±8.5 25.2±7.1 t=0.99 0.323 Alb （g/L） 41.3±2.7 41.2±2.8 t=0.35 0.727 PLT （×109/L） 196.2±53.1 157.4±53.0 t=5.99 <0.001
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表 3 显著肝组织病理学改变的单因素分析
Table 3. Univariate analysis of significant hepatic histopathological alterations
项目 肝脏显著炎症 显著肝纤维化 OR （95%CI） P值 OR（95%CI） P值 年龄 <30岁 1.00 1.00 30～39岁 0.51（0.22～1.18） 0.116 0.72（0.35～1.50） 0.386 ≥40岁 0.59（0.29～1.19） 0.142 1.05（0.56～1.99） 0.874 性别（男） 1.15（0.63～2.09） 0.649 1.17（0.68～2.01） 0.561 ALT（≥30/19 U/L） 2.61（1.45～4.68） 0.001 1.23（0.76～1.99） 0.405 HBV DNA（≥2 000 IU/mL） 2.59（1.40～4.80） 0.002 1.73（0.99～3.03） 0.055 LSM（≥6.0 kPa） 3.71（1.87～7.38） <0.001 2.02（1.23～3.31） 0.006
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表 4 显著肝组织病理学改变的多因素分析
Table 4. Multivariate analysis of significant hepatic histopathological alterations
项目 肝脏显著炎症 显著肝纤维化 OR（95%CI） P值 OR（95%CI） P值 年龄 <30岁 1.00 1.00 30～39岁 0.50（0.20～1.24） 0.134 0.74（0.35～1.57） 0.435 ≥40岁 0.51（0.23～1.12） 0.095 1.07（0.55～2.06） 0.848 性别（男） 1.14（0.62～2.48） 0.538 1.17（0.68～2.01） 0.561 ALT（≥30/19 U/L） 2.69（1.39～5.21） 0.003 1.13（0.66～1.91） 0.663 HBV DNA（≥2 000 IU/mL） 2.75（1.38～5.48） 0.004 1.82（1.01～3.32） 0.049 LSM（≥6.0 kPa） 4.57（2.17～9.62） <0.001 2.06（1.23～3.43） 0.006
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